The invention relates to a process for the racemization of enantiomerically pure N-acylamino acids using transition metal catalysts for the preparation of racemic N-acylamino acids of the formula (I).
Amino acids and their derivatives indisputably belong to the most important classes of organic compound. In addition to the biochemical importance, amino acid derivatives are of great economic interest as active compound intermediates, agrochemicals, food additives and industrial fine chemicals. Despite the development of enantioselective preparation processes, for example, by Schxc3x6llkopf (U. Schxc3x6llkopf, Top. Curr. Chem. 1983, 109, 65), Seebach (D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. 1996, 108, 2880), Evans (D. A. Evans, A. E. Weber, J. Am. Chem. Soc. 1987, 109, 7151; D. A. Evans, T. C. Britton, J. A. Ellman, R. L. Dorow, J. Am. Chem. Soc. 1990, 112, 4011), Williams (R. M. Williams, P. J. Sinclair, D. Zhai, D. Chen, J. Am. Chem. Soc. 1988, 110, 1547; R. M. Williams, Vol. 7, Pergamon Press 1989) and the newest method developments (N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997, 119, 445-446; Y. S. Park, P. Beak, J. Org. Chem. 1997, 62, 1574-1575; A. G. Myers, J. L. Gleason, T. Yoon, D. W. Kung, J. Am. Chem. Soc. 1997, 119, 656-673; B. M. Trost, Science 1991, 254, 1471-1477), in general xe2x80x9cclassical methodsxe2x80x9d such as the Strecker synthesis with subsequent N-acylation and resolution are used industrially for the preparation of unnatural amino acids. The advantage of three-stage processes of this type is in particular in the price and the availability of the starting materials and the practicability of the individual reaction steps.
Enzymatic resolutions of various N-acylamino acids are possible with a large number of functionalized N-acylamino acids in the presence of acylases. Compilations are found, for example, in J. P. Greenstein, M. Winitz in xe2x80x9cChemistry of the Amino Acidsxe2x80x9d John Wiley and Sons, London, 1961, Vol 1, 715-760; H. Keith, J. Dahmer, G. M. Whitesides, J. Am. Chem. Soc, 1989, 111, 6354-6364. Generally, in the resolution processes the undesired remaining enantiomer of the N-acylamino acid is racemized again after the resolution, so that in a multistage process almost quantitative yields of the desired enantiomerically pure amino acid are achieved. In the literature, to date acid catalysts are employed at relatively high temperatures as racemization catalysts for N-acylamino acids (DE 3334849). On account of the drastic reaction conditions and the nonspecific reactivity of the acid catalysts, in the case of sensitive functionalized N-acylamino acids side reactions occur which decrease the total yield and significantly complicate the product isolation. Alternatively to this, racemization can be carried out using stoichiometric amounts of ketene (DE 2740380). Because of the high toxicity and the impracticable manipulability of ketene, this method, however, is scarcely of practical use.
Against this background, the development of novel gentle racemization catalysts is of great interest. The object of the present invention was consequently to make available a process for the racemization of N-acylamino acids which proceeds under mild conditions.
Surprisingly, it has been found that enantiomerically pure or enantiomerically enriched N-acylamino acids can be racemized at the stereogenic center (xcex1-C center) under mild reaction conditions in the presence of transition metal catalysts.
The subject of the present invention is a process for the racemization of N-acylamino acids of the formula (I),
Rxe2x80x94CH(NR1COR2)CO2H xe2x80x83xe2x80x83(I) 
in which R, R1 and R2 independently of one another are a hydrogen and/or alkyl, alkenyl, alkynyl, aryl and/or heteroaryl radical, where alkyl can be an aliphatic carbon group having 1 to 18 carbon atoms, which can be linear, branched and/or alternatively cyclic, and alkenyl or alkynyl is a mono- or polyunsaturated aliphatic group having 2 to 18 carbon atoms, which can be branched or nonbranched, and aryl is a five-, six- or seven-membered aromatic ring, where this ring can be fused and can contain 0 to 3 heteroatoms such as N, O, S, comprising 4 to 14 carbon atoms, and in this case the alkyl and the aryl group can optionally carry up to six further substituents which independently of one another are hydrogen, alkyl, O-alkyl, OCO-alkyl, O-aryl, aryl, fluorine, chlorine, bromine, iodine, OH, CF3, NO2, NO, Sialkyl3, CN, COOH, CHO, SO3H, NH2, NH-alkyl, N-alkyl2, PO-alkyl2, SO2-alkyl, SO-alkyl, CF3, NHCO-alkyl, CONH2, CO-alkyl, COO-alkyl, NHCOH, NHCOO-alkyl, CO-aryl, COO-aryl, POaryl2, PO3H2, PO(O-alkyl)2, SO3-alkyl,
where alkyl and aryl have the abovementioned meaning, which comprises reacting, in a solvent, an enantiomerically enriched mixture or an enantiomerically pure compound of the formula (I), in the presence of a transition metal salt, transition metal complex or transition metal complex salt or of a mixture thereof comprising at least one element from the group consisting of Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, preferably at a temperature of 10-150xc2x0 C.
By a combination of the catalytic racemization described here with a crystallization of an enantiomer in the presence of a chiral resolution reagent or with an acylase-catalyzed deacylation, for the first time dynamic kinetic resolutions of racemic N-acylamino acids can also be carried out.
The process according to the invention can moreover be carried out very economically and both simply and rapidly. After completion of the reaction, the racemized product is purified by simple measures, e.g. by extraction or crystallization, or it is subjected directly as a crude product to a resolution, such as, for example, reaction with an acylase, crystallization using a chiral resolution reagent, such as a chiral base or direct crystallization. If appropriate, such a process can also be carried out in situ, so that a dynamic kinetic resolution results.
Further, with the aid of the method found an asymmetric transformation of N-acylamino acids, such as is described, for example, in Bull. Chem. Soc. Jpn. 1981, 54, 3286, can be carried out under markedly milder and more gentle conditions.
Preferably, in the compounds of the formula (I)
R, R1 and R2 independently of one another are hydrogen, (C4-C14)-aryl, (C1-C18)-alkyl, (C2-C18)-alkenyl or (C3-C18)-alkynyl, CnH2n-cycloalkyl where n=3-18, which can be branched or nonbranched and which can be substituted by 1-6 substituents which independently of one another are hydrogen, alkyl, O-alkyl, O-aryl, aryl, fluorine, chlorine, bromine, iodine, OH, NO2, CN, COOH, CHO, NH2, NH-alkyl, N-alkyl2, PO-alkyl2, SO2-alkyl, CF3, NHCO-alkyl, CONH2, CO-alkyl, NHCOH, NHCOO-alkyl, CO-aryl, COO-aryl, POaryl2, PO3H2, PO(O-alkyl)2, and aryl is a five-, six- or seven-membered aromatic ring, where this ring can be fused and can contain 0 to 3 heteroatoms such as N, O, S, comprising 4 to 14 carbon atoms.
Particularly preferably, in the compounds of the formula (I)
R, R1 and R2 independently of one another are hydrogen, (C5-C12)-aryl, (C1-C16)-alkyl, (C2-C16)-alkenyl or (C3-C16)-alkynyl, CnH2n-cycloalkyl where n=3-16, which can be branched or nonbranched and which can be substituted by 1-4 substituents which independently of one another are hydrogen, alkyl, O-alkyl, O-aryl, aryl, fluorine, chlorine, bromine, iodine, OH, NO2, CN, COOH, CHO, NH2, NH-alkyl, N-alkyl2, CF3, NHCO-alkyl, CONH2, CO-alkyl, NHCOH, NHCOO-alkyl, CO-aryl, COO-aryl, and aryl is a five-, six or seven-membered aromatic ring, where this ring, can be fused and can contain 0 to 3 heteroatoms such as N, O, S, comprising 4 to 12 carbon atoms.
Very particularly preferably, in the compounds of the formula (I)
R, R1 and R2 independently of one another are hydrogen, (C5-C10)-aryl, (C1 C14)-alkyl, (C2-C14)-alkenyl or (C3-C14)-alkynyl, CnH2n-cycloalkyl where n=3-14, which can be branched or nonbranched and which can be substituted by 1-3 substituents which independently of one another are hydrogen, alkyl, O-alkyl, O-aryl, aryl, fluorine, chlorine, bromine, iodine, OH, NO2, CN, COOH, CHO, NH2, NH-alkyl, N-alkyl2, CF3, NHCO-alkyl, CONH2, CO-alkyl, CO-aryl, COO-aryl, and aryl is a five-, six- or seven-membered aromatic ring, where this ring can be fused and can contain 0 to 3 heteroatoms such as N, O, S, comprising 4 to 10 carbon atoms.
Examples of N-acylamino acids which can be racemized by the process according to the invention, without these being restricted thereto, are: N-acylvaline, N-acylvinylglycine, N-acylphenylalanine, N-acylmethionine, N-acylphenylglycine, N-acyl-4-hydroxyphenylglycine, N-acyl-3-pyridylalanine, N-acyltryptophan, N-acyllysine, N-acyl-tert-leucine, N-acylproline, N-acylcyclohexylglycine, N-acylserine, N-acylphosphinothricin. In this case, acyl is preferably acetyl, benzoyl, phenylacetyl, methoxyacetyl, chloroacetyl, and propionyl.
Preferably, the racemization catalysts used are salts, complexes or salts of the complexes of the transition metals Fe, Ru, Ir, Rh, Co and Pd.
Particularly preferred racemization catalysts are compounds of the elements Ru, Ir, Rh, Pd. Examples of complexes of these elements which can be employed are: [Rh(cod)Cl]2, (CO)2Rhacac, Rh(cod)acac, Rh(PPh3)3Cl, Ir(PPh3)3Cl, [Ru(p-cymene)Cl]2, Rh(cod)2BF4, [Ru(CO)2CH3CO2]n, Ru(CO)(H2)(PPh3)3, Ru(cod)Cl2, Ir(cod)2BF4, IrCl(CO)(PPh3)2, Ir(CO)2acac, Ru(acac)3, Pd(PPh3)4, PdCl2(CH3CN)2, Pd(OAc)2, PdCl2, Li2PdCl4, Pd2(dba)3.
As a rule, it is advantageous if the racemization catalyst is present in homogeneous form. However, heterogeneous or heterogenized metal complexes can advantageously be employed, in particular at reaction temperatures of greater than 100xc2x0 C. Heterogeneous catalysts to be employed are, for example, rhodium, iridium or ruthenium on supports such as activated carbon, alumina, silica gel and titanium dioxide. For the stabilization but also for increasing the activity of the catalysts, the addition of nitrogen-containing and/or phosphorus-containing ligands, such as of amine and/or phosphine ligands, is advantageous. Typically employed phosphine ligands are triphenylphosphine, tricyclohexylphosphine, tri(tert-butyl)phosphine, TPPTS (tris(3-sulfonatophenyl)phosphine), tri-n-butylphosphine, bisdiphenylphosphinopropine, tri-o-tolylphosphine, trimethyl phosphate, diphenyl-2-pydridyl-phosphine, and bis(dicyclohexylphosphino)butane. Amine ligands which can be used, for example, are triethylamine, pyridine, bipyridine, tetramethylethylenediamine, triazacyclononane, and piperazine.
The reaction is expediently carried out in a solvent. Solvents which can be used are organic solvents or water. It may be advantageous to use mixtures of solvents. Suitable solvents are, for example, acetonitrile, butyronitrile, ethyl acetate, dimethoxyethane, acetone, THF, dioxane, hexane, tert-butyl methyl ether and tert-butanol, toluene, DMSO, chloroform and respective mixtures thereof. The proportion of N-acylamino acid in the solution is preferably 5-50%.
The N-acylamino acids are expediently prepared from the amino acid by known methods of acylation.
In the process according to the invention, the racemization catalyst is preferably employed in catalytic amounts with respect to the N-acylamino acid. Generally, between 0.2 and 0.0001 equivalent based on N-acylamino acid, preferably 0.15 to 0.001 and particularly preferably 0.1 to 0.001 equivalent, is used.
The present invention is to be illustrated in greater detail by means of the following examples, without restricting the invention thereto.